Thromboxane A2 (TXA2) is an extraordinarily potent platelet aggregating and vasoconstricting agent, and has been implicated in hemostasis, thrombosis, and ischemia. However, the elusive character of the molecule impedes detailed study of its physiological roles. The extreme instability of TXA2 under physiological conditions (t1/2 = 32 sec) has thus far precluded its isolation from natural sources. Indeed, even the structure of the molecule is not yet definitely established; the accepted structure has been inferred from the mode of biosynthesis and the structures of stable degradation products. From these considerations, TXA2 emerges as an unusually significant target for chemical total synthesis. Although several stable TXA2 analogues have now been prepared, no progress toward the synthesis of TXA2 itself has been reported to date. To confirm the proposed structure and generate invaluable samples for biomedical studies, we propose herein the total synthesis of thromboxane A2. Since the instability of TXA2 is attributed to its highly reactive dioxa-bicyclo[3.1.1]heptane ring system, we are investigating the synthesis of a model compound containing this bicyclic acetal moiety. To our knowledge, no compound containing this ring system has ever been prepared. The key step in our approach is a novel cyclization of a suitably functionalized 1,1-dialkoxymethyllithium compound. We will then undertake a chiral synthesis of TXA2 itself. The bicyclic acetal would be generated in the last step of the scheme, using our 1,1-dialkoxymethyllithium methodology. A convergent approach to the cyclization substrate is described. The lower side chain will be introduced via a new stereoselective addition reaction of a chiral vinylmetallic species. Introduction of the upper side chain would be achieved using a novel Z-allylpotassium reagent. The total synthesis of thromboxane A2 would enormously simplify the study of its physiological roles, leading to significant gains in understanding of thrombotic disease and promoting the development of effective thromboxane antagonists.
